72-hour slow-release and higher oral bioavailability can be realized for the oral form of the poorly soluble drug insofar as such techniques as ordered mesoporous nanoparticles technique, hydrophilic gel matrix technique and solid dispersion technique are integrally adopted.
Due to its poor solubility in water, the poorly soluble drug is characteristic of being poorly absorbed by human body, fast rate of elimination, frequent occurrence of peak and trough phenomenon of the plasma concentration, low oral bioavailability, and hard to diversify its dosage form. Controlled release preparation of drugs is being widely used in virtue of its less total amount and frequency of administration, which consequently avoids peak and trough phenomenon of plasma concentration, reduces toxic and side effects and improves patients' adaptability [see: Lee K, Nguyen T, Hanley T, et, al. “Nanostructure of Liquid Crystalline Matrix Determines in vitro Sustained Release and in vivo Oral Absorption Kenetics for Hydrophilic Model Drugs.” International Journal of Pharmaceutics 365.1-2 (2009):190.; Wang Jiexin, Wang Zhihui, Chen Jianfeng, et, al. “Direct Encapsulation of Water-soluble Drug into Silica Microcapsules for Sustained Release Applications.” Materials Research Bulletin 43.12 (2008): 3374.]. Therefore, the defects such as great fluctuation of plasma concentration and frequent administrations of the poorly soluble drug can be effectively avoided when the drug is prepared in the controlled release form after having been solubilized. However, since the poorly soluble drug is not able to completely dissolve in water when being prepared in the controlled release form, an in advance solubilization is needed. The solubilized drug then can be used as the raw material for preparation of various forms of the slow-release drug. Techniques that can be utilized for solubilization of the poorly soluble drug include: solid dispersion technique, cyclodextrin inclusion technique, miceller solubilization technique and microemulsion technique [see: Shen Song, Xu Ximing, Yu Jiangnan. “Research Development on Solubilization of Poorly Water-soluble Drugs and Preparation of Its Controlled Release Forms.” Chinese Pharmaceutical Affairs 21.3 (2007):196.; Guo Shengrong, Guo Li. “Effects of PVP K30 on Aqueous Solubility and Dissolution Properties of Daidzein.” Journal of Chinese Pharmaceutical Sciences 13.1 (2004) :42.; Z. Zuo, Y. K. Tam, J. Diakur, et, al. “Hydroxypropyl-beta-cyclidextrin-flutamide Inclusion Complex. II. Oral and Intravenous Pharmacokinetics of flutamide in the Rat.” J Pharm Sci 5.3 (2002): 292.; C. M. Fernandes, M. T. Vieira, F. J. B. Veiga. “Physicochemical Characterization and in vitro Dissolution Behavior of Nicardipine-cyclodextrins Inclusion Compounds.” European Journal of Pharmaceutical Sciences 15.1 (2002): 79.; Kang Moo Huh, Sang Cheon Lee, Yong Woo Cho. “Hydrotropic Polymer Micelle System for Delivery of Paclitaxel.” Journal of Controlled Release 101.1-3 (2005):59.].Compared with other said methods, solid dispersion technique is more extensively utilized in virtue of its simple preparation procedure and outstanding solubilization effect [see: Wei Zhenping, Mao Shirui, Bi Dianzhou, et, al. “Dissolution Improvement of Cisapride by Solid Dispersion with HPMC,” Journal of Chinese Pharmaceutical Science 13.4 (2004):254.; Cui Fude, Yang Mingshi, Jiang Yanyan. “Design of Sustained-release Nitrendipine Microspheres Having Solid Dispersion Structure by Quasi-emulsion Solvent Diffusion Method.” Journal of Controlled Release 97.3 (2003):375.]. After having been solubilized, the poorly soluble drug can be either prepared in the conventional controlled release formulation or mixed with other controlled release materials at an appropriate ratio to prepare matrix type, osmotic pump type, or membrane-controlled type of formulations.
In recent years, much attention has been attracted to the special structure and features of the mesoporous material. It refers to a type of material containing multiple pores with diameter between 2 to 50 nanometers. A mesoporous material can be disordered or ordered according to the structure of the mesopores. The ordered mesoporous material enjoys the following structural characteristics: 1. long-range structure being ordered; 2. pore size distribution being narrow and adjustable between 1.5 to 10 nanometers; 3. specific surface area reaching as high as 1000 m2/g; 4. high porosity and 5. rich unsaturated radicals on its surface. When used as a drug carrier, the ordered mesoporous material presents the following advantages: 1. being nontoxic, nonphysioactive and biocompatible; 2. having evenly distributed, adjustable pore canals, within which its rich silanic radicals act as active sites for combining organic guest molecules; the drug molecules, through combining with these radicals, distribute within the canals evenly as well. Since the drug is absorbed within the ordered mesoporous material, it acts in a slow-release way; 3. protecting the integrity of molecular structure of the drug. Therefore, an ideal controlled release can be achieved for the hydrophobic drug when the mesoporous material is adopted as the controlled release carrier. The release effect varies in relation to the structure of the pore canal of the ordered mesoporous material.
On the basis of “triple release” mechanism comprising quick-release of the solid dispersion, regular slow-release of the hydrophilic gel matrix and the long-acting, slow-release of the ordered mesoporous material, this invention discloses a new method for preparing the slow-release formulation of the poorly soluble drug that realizes 72-hour continuous release and enhances its oral bioavailability; the formulation prepared with this method simultaneously encompasses quick-release and double slow-release, and presents double pharmacokinetic advantages of high-efficacy and long-action.